Method of treating pre-menstrual syndrome using chromium

ABSTRACT

The method of this invention is directed to a treatment of depression in men and women and to a treatment of pre-menstrual syndrome (PMS) in women by administering to a patient a therapeutically effective amount of chromium in a pharmaceutically acceptable form either alone or in conjunction with the administration of a standard antidepressant composition, such as a selective serotonin reuptake inhibitor composition. Chromium, preferably in the form of chromium picolinate, is administered to the patient at dosages in a preferred range of about 200 to about 500 micrograms chromium.

TECHNICAL FIELD

The present invention relates generally to a treatment for depressionand to a treatment of pre-menstrual syndrome, and more particularly tothe treatment of depression using chromium and to the treatment ofpre-menstrual syndrome using chromium. The present invention alsoparticularly relates a method of improving the effectiveness of anantidepressant composition by administering chromium to a patientconcurrently with the administration of an antidepressant composition tothe patient.

BACKGROUND ART

It will be appreciated by those having ordinary skill in the art thatdepression is a difficult mental disorder to treat. Patients having sucha disorder are often reluctant to seek the medical attention necessaryto diagnose the disorder. Such reluctance is often related to thepatient's fear of the stigma associated with seeking psychiatric help orto the patient's feelings of worthlessness associated with depression.Moreover, once patients seek competent psychiatric help, it is difficultto successfully treat the disorder through psychoanalytic approachesalone.

In the Diagnostic and Statistical Manual of Mental Disorders, FourthEdition, (DSM IV) published by the American Psychiatric Association,depressive disorders are classified under mood disorders and are dividedinto three types: major depressive disorder, dysthymic disorder anddepressive disorder not otherwise specified. Major depressive disorderand dysthymic disorder are differentiated based on chronicity, severityand persistence. In major depression the depressed mood must be presentfor two weeks. In dysthymic disorder the depressed mood must be presentmost days over a period of two (2) years. Usually major depressivedisorder is characterized by its sharp contrast to usual functioning. Aperson with a major depressive episode can be functioning and feelingnormally and suddenly develop severe symptoms of depression. By contrasta person with dysthymic disorder has chronic depression with less severesymptoms than major depression.

In an effort to treat depression, a variety of antidepressantcompositions have been developed. Among these are the selectiveserotonin reuptake inhibitors (SSRI), such as sertraline (registeredtrademark ZOLOFT® - Pfizer), fluoxetine (registered trademark PROZAC® -Eli Lilly), paroxetine (trade name PAXIL™ - Smith Kline Beecham) andfluvoxamine (trade name LUVOX™). Other examples of antidepressantcompositions include tricyclic antidepressants such as that sold underthe registered trademark ELAVIL® (Merck, Sharpe and Dohme), aminoketoneantidepressants such as bupropion, and lithium, a metal used to treatbipolar disorder. However, these drugs are very potent, often generatingproblematic side effects such as lethargy, clouded thinking and a lackof ability to concentrate.

Fluoxetine is also known to be efficacious in the treatment ofdysmenorrhea and pre-menstrual syndrome (PMS). Steiner et al., NewEngland Journal of Medicine 332:1529-34 (1995). The symptoms of PMSinclude dysphoria, craving for carbohydrates, exhaustion, muscle achesand cramps, among others. A detailed description of the symptoms of PMScan be found in the Diagnostic and Statistical Manual of MentalDisorders, Fourth Edition, (DSM IV) published by the AmericanPsychiatric Association. However, approximately forty percent (40%) ofwomen who are suffering from PMS do not have a positive response tofluoxetine when treated with it.

Chromium, in its pharmaceutically acceptable trivalent form, has beenused in the treatment of overeating as it is documented to controlappetite. Trivalent chromium is commercially available as chromiumpicolinate. Chromium has also been documented as playing a role infacilitating the action of insulin in the body. In this regard, toxicityconcerns relating to chromium have been demonstrated to be quite low.

There has been no description of the use of chromium in the treatment ofdepression or in the treatment of pre-menstrual syndrome.

A method of treating neurological and mental disorders was described inSandyk U.S. Pat. No. 5,470,846. However, the method of this referenceincludes the application to the brain of a patient of a sufficientamount of an AC pulsed magnetic field of proper intensity and frequencyto treat the disorder. In conjunction with the application of the ACpulsed magnetic field, a stimulant to facilitate the transport oftryptophan into the brain is administered. Chromium, preferably in theform of chromium picolinate, is described as a stimulant. However, whenthe disclosure of this application of chromium is taken as a whole, thedeficiencies become apparent. First of all, the application of the ACpulsed magnetic field is required in the method. Additionally, apatient, particularly in the case of depression, may be resistant toaccepting such a complex treatment.

Therefore, what is needed then is an effective, pharmacologically-basedtreatment for depression and for pre-menstrual syndrome that potentiatesthe action and reduces the side effects of known compositions used inthe treatment of these disorders. Such a method of treatment is lackingin the prior art.

DISCLOSURE OF THE INVENTION

The method of this invention comprises the treatment of depression byadministering to a patient a therapeutically effective amount ofchromium in a pharmaceutically acceptable form either alone or inconjunction with the administration of a standard antidepressantcomposition. The administration of the pharmaceutically acceptable formof chromium does not need to be carried out in the presence of applyinga magnetic field to a patient and is desirably carried out in theabsence of any such application of a magnetic field.

Any standard antidepressant composition is contemplated to be within thescope of this invention. Among these are the selective serotoninreuptake inhibitors (SSRI), such as sertraline (registered trademarkZOLOFT® - Pfizer), fluoxetine (registered trademark PROZAC® - EliLilly), paroxetine (trade name PAXIL™- Smith Kline Beecham) andfluvoxamine (trade name LUVOX™). Other examples include tricyclicantidepressants such as that sold under the registered trademark ELAVIL®(Merck, Sharpe and Dohme), aminoketone antidepressants such asbupropion, and lithium, a metal used to treat bipolar disorder.

Chromium is administered one to three times a day. A preferred range isabout 50 to about 1,000 μg daily. A more preferred range is about 100 toabout 600 μg daily. A most preferred range is about 200 to about 500 μgchromium daily. The preferred form of chromium is chromium picolinate.

Stated differently, a preferred range is about 1 μg to about 10 μgchromium per kilogram body weight of the patient daily. A more preferredrange is about 2 μg to about 8 μg chromium per kilogram body weight ofthe patient daily. A most preferred range is about 4.5 μg to about 6 μgchromium per kilogram body weight of the patient daily.

Also, contemplated to be within the scope of this invention are a methodof treating dysmenorrhea, a method of treating pre-menstrual syndrome,and a method of treating alcoholism. These methods comprise theadministration of a therapeutically effective amount of chromium in apharmaceutically acceptable form to a patient in need thereof. Similardosage ranges as those presented above are applicable to these methods.

Accordingly, it is an object of this invention to provide a method oftreating depression that is pharmacologically-based.

It is a further object of this invention to provide a method of treatingdepression that is more appealing to patients.

It is yet a further object of this invention to provide a method forimproving the effectiveness of anti-depressant compositions.

It is yet another object of this invention to provide a method oftreating alcoholism.

It is still another object of this invention to provide a method oftreating pre-menstrual syndrome (PMS).

Some of the objects of the invention having been stated hereinabove,other objects will become evident as the description proceeds, whentaken in connection with the accompanying drawings as best describedhereinbelow.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a graphical representation of the Beck Scale data from PatientNo. 1 in Example 1.

FIG. 2 is a graphical representation of SCL-90 Scale data from PatientNo. 1 in Example 1.

FIG. 3 is a graphical representation of the SCL-90 Subscale data forPatient No. 1 in Example 1.

FIG. 4 is a graphical representation of the Beck Scale data for PatientNo. 2 in Example 2.

FIG. 5 is a graphical representation of the SCL-90 Subscale data fromPatient No. 2 in Example 2.

FIG. 6 is a graphical representation of the severity of the symptoms ofpre-menstrual syndrome as experienced by Patient No. 4 when takingparoxetine and lithium.

FIG. 7 is a graphical representation of the severity of the symptoms ofpre-menstrual syndrome from Patient No. 4 in Example 4 when taking nomedication.

FIG. 8 is a graphical representation of the severity of the symptoms ofpre-menstrual syndrome when Patient No. 4 was taking paroxetine andchromium picolinate.

DETAILED DESCRIPTION OF THE INVENTION

As noted above, there are three types of depression generallycharacterized in the art, major depression, dysthymic disorder, ordysthymia, and depressive disorder not otherwise specified. Majordepression is characterized by peak episodes of extreme depression.During a peak episode, the patient may suffer from dysphoria, cravingfor carbohydrates, exhaustion, muscle aches, and dangerously suicidalnotions.

Dysthymia is characterized by chronic low moods that can last for longperiods of time in the life of the patient, such as 20 years. Dysthymiais further characterized by lack of passion for things in the sufferer'slife, including work, food, and/or sexual relations, and by dysphoria.

Diagnosis criteria for dysthymia and major depression are more fullyexplained in the Diagnostic and Statistical Manual of Mental Disorders,Fourth Edition, (DSM IV) published by the American PsychiatricAssociation, the contents of which are herein incorporated by reference.

The method of this invention comprises the treatment of depression byadministering to a patient a therapeutically effective amount ofchromium in a pharmaceutically acceptable form either alone or inconjunction with the administration of a standard antidepressantcomposition. The administration of the pharmaceutically acceptable formof chromium does not need to be carried out in the presence of applyinga magnetic field to a patient and is desirably carried out in theabsence of any such application of a magnetic field.

In the methods of the instant invention, chromium is administered one tothree times a day. The preferred form of chromium, chromium picolinate,is commercially available. An acceptable source is marketed under thetrademark Nature Made®. From this source each tablet contains 200 μgchromium from chromium picolinate. The tablets from this source alsoinclude dibasic calcium phosphate, cellulose and magnesium stearate. Adaily nutritional value from chromium is yet to be established.

Thus, a preferred dosage range for chromium is about 50 to about 1,000μg daily. A more preferred range is about 100 to about 600 μg daily. Amost preferred range is about 200 to about 500 μg chromium daily. Thepreferred form of chromium is chromium picolinate.

Stated differently, a preferred range is about 1 μg to about 10 μgchromium per kilogram body weight of the patient daily. A more preferredrange is about 2 μg to about 8 μg chromium per kilogram body weight ofthe patient daily.

Most preferred dosage ranges of chromium are those doses sufficient todeliver from about 4.5 to about 6 μg of chromium per kilogram (kg) ofbody weight. This dosage range is generally several fold greater thanthat contained in most commercially available multi-vitamin and mineralpreparations. This amount results in a plasma chromium level between 0.9μg/liter to 2.1 μg/liter. The plasma level will vary depending on thelevel of exercise, i.e., the more one exercises, the more chromium isrequired to maintain plasma levels.

To more fully characterize dosage information, the most preferred dosagerange is calculated based on consuming enough chromium picolinate todeliver about 200 to about 500 μg elemental chromium. According tostandard stoichiometric calculations, in delivering 200 μg elementalchromium, approximately 1600 μg chromium picolinate is consumed in astandard commercial preparation.

It is also preferable to take the last, or only, daily dose of chromiumeight (8) hours prior to sleep to avoid insomnia. It is also noted thatdiabetics and hypoglycemics should use chromium only under a physician'ssupervision.

Commercially available tubes for the collection of blood can containsignificant amounts of chromium. To avoid contamination, plasma levelsof chromium should be determined from blood collected in heparinized orEDTA tubes.

Also, contemplated to be within the scope of this invention are a methodof treating dysmenorrhea (painful menses), a method of treatingpre-menstrual syndrome (PMS), and a method of treating alcoholism oralcohol craving. These methods comprise the administration of atherapeutically effective amount of chromium in a pharmaceuticallyacceptable form to a patient in need thereof. Similar dosage ranges asthose presented above are applicable to these methods.

Any standard antidepressant composition is contemplated to be within thescope of this invention. Among these are the selective serotoninreuptake inhibitors (SSRI), such as sertraline (registered trademarkZOLOFT® - Pfizer), fluoxetine (registered trademark PROZAC® - EliLilly), paroxetine (trade name PAXIL™- Smith Kline Beecham) andfluvoxamine (trade name LUVOX™). Other examples include tricyclicantidepressants such as that sold under the registered trademark ELAVIL®(Merck, Sharpe and Dohme), aminoketone antidepressants such asbupropion, and lithium, a metal used to treat bipolar disorder.

In the foregoing examples, chromium picolinate is preferred source ofchromium. Other acceptable sources include chromium citrate, chromiumchloride and chromium acetate. Other pharmaceutically acceptable formsof chromium would be apparent to one having ordinary skill in the art.

The following examples are set forth to illustrate the subjectinvention. The examples should not be considered as limiting, the scopeof the invention being defined by the claims appended hereto.

EXAMPLE 1 Treatment of Dysthymia

Patient No. 1 was a 50-year old white male who, after a series ofpsychoanalysis/psychotherapy sessions, was diagnosed as suffering fromdepression in the form of dysthymia. Patient No. 1 experienced a chroniclow mood with markedly diminished interest and pleasure in allactivities including work, eating, and sexual relations.

Initially, Patient No. 1 was treated only with the known antidepressantsertraline (sold under the registered trademark ZOLOFT®). Sertraline isa selective serotonin reuptake inhibitor. Sertraline was administered inamounts from 50 to 150 mg qd(per day); and it was ultimately determinedthat the ideal dose for this patient was 125 mg qd (per day). Sertralineprovided some relief of the symptoms of dysthymia; but, often made thepatient sluggish in his daily activities and made his thinking cloudy,or fuzzy.

Independent of the sertraline treatments, the patient began taking avitamin and mineral supplement that included a series of components.While taking this vitamin and mineral supplement, the patient noticed amarked improvement in his condition. As such improvement was unexpected,a study of the components of the mineral preparation was undertaken.During this study Patient No. 1 stopped taking the compositepreparation.

In this study, Patient No. 1 took one component of the preparation at atime according to a schedule of one pill a day for five days, Mondaythrough Friday. At the end of each week, he filled out two self-ratingscales that are used in the diagnosis and monitoring of depression.These scales are the Beck Scale and the SCL-90 Scale, both of which arewell known in the field of psychiatry and psychotherapy. Patient No. 1continued to take sertraline at 125 mg per day. During the study,Patient No. 1 was not informed of what he was taking.

During the week prior to the beginning of the study, Patient No. 1 tooksertraline at 125 mg qd alone. He experienced loss of energy, disturbedsleep, and awaking tired. He also experienced a loss of muscle strengthwhen exercising, muscle tightness in the neck and shoulders, hard bowelmovements, frequent mild headaches, ringing in the ears (which hasworsened since starting the sertraline), lack of focus on anyactivities, and loss of desire for sex. No Beck Scale or SCL-90 Scalewas given prior to this period.

During the first week of the study, Patient No. 1 received a placebo ofvitamin C along with the 125 mg of sertraline each day for five days.His condition continued to worsen. His thought processes were cloudy,and he had trouble concentrating which interfered with his work. Duringa meeting at his work, he had trouble following the discussions. Asdemonstrated in the graph in FIG. 1, his total Beck score was +10,indicating a depressed condition.

During the second week, Patient No. 1 received chromium in the form ofchromium picolinate. Patient No. 1 took 200 μg of chromium from chromiumpicolinate per day along with 125 mg of sertraline. He noticed adramatic, certain and immediate relief of symptoms. He observed anincrease in energy and his appetite was under control. His appearancewas relaxed and cheerful, as observed by the inventor in a meetingapproximately three days after Patient No. 1 began to take chromium. Thetotal Beck score at the end of the week was 0, indicating no depression.

During the third week, Patient No. 1 took 125 mg of sertraline qd. andone guarana pill each day. Guarana was selected as the next componentbecause it contains caffeine. During this week, he became dehydrated,had a slight headache and sore muscles, suffered from disturbed sleepand loss of energy, and his carbohydrate craving returned. He noted thathe felt like he had taken too much caffeine. The Beck score at the endof this week was a +2.

During the fourth week, Patient No. 1 took 125 mg sertraline qd andginseng. Patient No. 1 observed that this week was better than lastweek, but not as good as the week before. He felt low on energy anddehydrated. At the end of this week, no chromium was detectable in hisplasma. His Beck score was also +1.

During the fifth week, Patient No. 1 took selenium and sertraline 125 mgqd. During this week, he felt agitated, as when he had consumed too muchcaffeine. He also did not feel rested when he awoke from sleep.

At this point, the study was ceased. The patient inquired as to what hewas taking during week 2 and was informed that he was taking chromiumpicolinate. On his own initiative, he consumed 400 μg of chromiumpicolinate and immediately felt much better. Patient No. 1 thencontinued to take 400 μg of chromium of chromium picolinate per day (200μg twice daily or b.i.d.). Further, the patient discontinued thesertraline treatment to further characterize the relationship betweenchromium and sertraline. During this week, the patient noted that hissleep was much improved, that his mind was clearer than when he wastaking sertraline, that he did not crave food or alcohol, and that forthe first time in years he was hopeful about the future. At this pointin the study, his plasma chromium level was 0.9 μg/L.

For Patient No. 1, a potential adverse side effect was observed. Thepatient reported that after taking 200 μg of chromium from chromiumpicolinate late in the day, his sleep was disturbed. He thereforedecided to take it no later than 3:00 p.m. He then reported that heslept much better after taking the second dose of chromium picolinateearlier in the day.

The patient's progress was tracked over an additional six-week period.The patient stated that he had felt the best he had felt in a decade. Hecharacterized himself as feeling good mentally and physically. He statedthat he began to feel normal. He felt better when taking the chromiumpicolinate alone than when taking chromium picolinate and sertraline atthe same time. The patient stated that he felt a "a bit slowed down" andhis thinking was dulled when he taking sertraline in addition to thechromium picolinate.

Patient No. 1 further observed that during a crisis period at workduring the last week of the study described herein, he increased hischromium from chromium picolinate intake to 200 μg t.i.d., or threetimes daily. Within an hour, he noticed immediate improvement and wasable to deal with his crisis.

The series of events described in the above example are more fully setforth in the graphs in FIGS. 1 and 2. FIG. 1 is a bar graph displayingthe scores on the Beck Scale, a self-rating scale for depression, at theend of each weekly treatment.

FIG. 2 is a bar graph of the total score on the SCL-90 Scale. The SCL-90is composed of 90 questions. It is designed to measure symptoms ofsomatization, obsessive-compulsive behavior, interpersonal sensitivity,depression, anxiety, hostility, phobic anxiety, paranoid ideation, andpsychoticism. It is noted that the grand total of scores on each Fridayclosely parallels the results of the Beck Scale.

FIG. 3 is a graph of three subscales of the SCL-90 (somatization,obsessive-compulsive, and depression). These subscales reflect thegreatest changes. The marked elevation on the somatization scale duringthe week after chromium picolinate was stopped may have been due to thecaffeine effect of guarana and/or lack of chromium picolinate. It isnoted that the positive reading during the last week of the therapy wasdue to Patient No. 1 experiencing certain unpleasant and unwantedthoughts regarding the crisis at his work referenced above. There was noreturn of somatic symptoms of depression.

Treatment of alcoholism or alcohol craving

During the later stages of the study described above, when Patient No. 1was taking chromium picolinate alone, he also noticed a change in hisability to tolerate alcohol. Both of his parents were alcoholics so heguarded carefully against this outcome by drinking infrequently.

Despite this effort, he often experienced intense cravings for alcohol.Prior to his treatment with chromium, when he consumed alcohol, he couldonly drink it by gulping it. He experienced rapid intoxication,unpleasant feelings, and a severe hangover the next day. Since treatmentwith chromium picolinate began as described above, he observedsignificantly diminished alcohol cravings. He also observed that hecould drink in moderation, without having a severe hangover the nextday.

Thus, a method of treating alcoholism or alcohol cravings iscontemplated to be within the scope of this invention.

EXAMPLE 2 Treatment of Dysthymia

Patient No. 2 was a 25-year old single white female. She is the daughterof Patient No. 1. She complained of weight gain, hyperphagia,hypersomnia, loss of interest in sex, irritability and an inability toconcentrate. She stated that she had been seeing psychotherapists sinceshe was 13 years old, but had no success in dealing with her depression.She was also diagnosed as having dysthymia.

She had taken sertraline in the amount of 50 mg qd. with little help.This dosage was increased to 100 mg qd. which proceeded for a period offive weeks. She was still symptomatic of depression, but felt better.She was not as weepy and her outlook was less negative. Her interest insex was increased. Her appetite remained the same. The sertralinetreatment improved her interest in a former hobby, reading.

Patient No. 2 then began a similar study as that described above forPatient No. 1. For the first week, she took one vitamin C tablet dailyalong with 100 mg of sertraline. Her depression appeared to worsen asreflected by her grand total Beck score of +12 and her SCL-90 +4 as morefully portrayed on the FIG. 5. She suggested that it was more difficultto more accurately evaluate women because of PMS.

During the second week, Patient No. 2 started 200 μg of chromium fromchromium picolinate per day and continued 100 mg sertraline per day. HerSCL-90 score demonstrated a definite improvement. She wrote on her BeckScale that her appetite was less.

For week three she took guarana and continued sertraline at 100 mg perday. She noted that she did not feel as well during this week as theprevious week. Week three was also the start of her menstrual cycle inwhich she normally experienced PMS.

During the fourth week she took ginseng and continued sertraline at 100mg per day. During the middle of this week she complained of low energy,headache, restlessness, and initial insomnia. She stated that shedefinitely had less energy than week two when she was taking chromiumpicolinate.

During week five she began taking St. John's Wort, a herb believed tohave antidepressant effects. She also continued sertraline at 100 mg perday. No positive response was observed.

During week six she began taking selenium and continued 100 mgsertraline per day. Her food craving returned and she generally did notfeel well. At this point, Patient No. 2 became impatient with this studyand wished to resume taking the medication that was effective. Shetherefore discontinued taking selenium and began taking chromiumpicolinate at 200 μg per day beginning the Monday of the next week.

Within two days she felt better and had no symptoms. She considered thestudy over and therefore did not take either the Beck Scale of theSCL-90. It was estimated via a telephone interview that her Beck Scalewas +2. Four days following her resuming treatment with chromiumpicolinate her plasma chromium was 0.8 μg/L.

Patient No. 2 continued to take sertraline along with chromiumpicolinate because of a stressful situation at her workplace. Despitethis added stress at work, she noted that she was able to function muchbetter than in the past. She stated that things just did not seem tobother her as much as they used to bother her.

Treatment of Pre-menstrual Syndrome (PMS)

While Patient No. 2 was taking chromium picolinate according to thedosages described above, she further observed that her menses was lessproblematic. She said that she had less carbohydrate craving during theweek before, that she was less irritable, that her dysphoria wasrelieved, and that her usual cramps were non-existent. Thus, an aspectof the present invention includes the treatment of pre-menstrualsyndrome (PMS), or dysmenorrhea (problematic and/or painful menses),comprising administering chromium in a preferred dose of 200 μg per dayto a patient in need thereof.

For Patient No. 2, FIG. 5 presents Patient No. 2's Beck Scale totalscores, and FIG. 6 presents a graph of the four subscales ofsomatization, obsessive-compulsive, depression, anxiety on the SCL-90Scale.

EXAMPLE 3 Treatment of Severe Dysthymia

Patient No. 3 was a 42-year old divorced man experiencing chronicsuicidal depression for about 15 years. For as long as the patient canremember, he has had episodic, mild-to-moderate mood swings.Approximately 15 years ago his condition worsened and he was depressedalmost daily. His thoughts were slowed down, he felt intensely sad,guilty, worthless, confused, and desperate. Over a period ofapproximately two years he underwent therapy with a social worker andpsychotherapy with a psychiatrist, with little positive results. Nopharmacotherapy was involved in either of these treatments.

Initially, Patient No. 3 met with the inventor and identified achildhood source as a partial cause of his depression, low self-esteemand dysfunctional thinking. Although he appreciated the insights gainedthrough the psychoanalysis/psychotherapy with the inventor, hisdepression persisted unabated. He was rejected by his girlfriend andbecame frighteningly suicidal.

Approximately eight months prior to the beginning of the treatment asdescribed below, he began taking 50 mg of ELAVIL® (a registeredtrademark for Merck, Sharpe and Dohme for the antidepressant,amitryptline HCl, a tricyclic antidepressant) per day which helped himsleep and allowed him, in his words, to think more rationally. Withinsix months he developed a tolerance to the drug and it was increased to100 mg per day with no effect. He stopped ELAVIL® and started bupropion100 mg b.i.d and lithium 300 mg t.i.d. Bupropion is an aminoketoneantidepressant, and lithium is a metal used to treat bipolar disorder.

The bupropion treatment was discontinued because he developedinvoluntary muscle twitches. His condition was desperate andlife-threatening. He was therefore prescribed sertraline at 100 mg qdand was given 12 200 μg pills of chromium picolinate with instructionsto take one pill b.i.d., or twice daily.

Patient No. 3 observed that after four to five days there was aperceptible change in his mood. He stated that he felt close tocontentment and might be there soon.

Thus, another aspect of this invention is that administration ofchromium in conjunction with the administration of a selective serotoninreuptake inhibitor (SSRI) like sertraline reduces the delay in the lagtime normally associated with an SSRI. Stated differently, there is lagtime of normally 30 days before the SSRI's effect on depression isnoted. In this case, Patient No. 3 experienced relief of symptoms withinfour to five days.

Two to three days after he took the last chromium picolinate tablets hebegan to feel as if he were slipping back and began feeling sad andpessimistic. He was then given a three-week supply of chromiumpicolinate so that he could take one pill providing 200 μg of chromiumfrom chromium picolinate twice daily. Within a matter of days, PatientNo. 3 noted that he rebounded and felt better than he had felt in manyyears.

He further observed that he felt like himself again and that he feltcontent in many ways. He stated that he had gained control of his lifethat he had felt deprived of for so long. He noted that instead ofobsessing for many hours over his low mood and past mistakes, he wasable to focus on practical matters. He became optimistic about hisfuture and about his artistic endeavors. He also felt as if his mind wasbecoming unburdened of much of the negative clutter that kept him fromdealing with his problems.

While taking chromium picolinate, Patient No. 3 was again rejected byhis girlfriend. Rather than slipping again into depression, he acceptedthis in stride and continued with his life.

Therefore, Patient No. 3, a patient suffering from severe dysthymia,noticed marked improvement after taking chromium picolinate in apreferred dosage providing chromium in the amount of 200 μg twice daily,or 400 μg per day.

EXAMPLE 4 Treatment of Major Depression, Dysphoria and Pre-MenstrualSyndrome

Patient No. 4 was a 45-year old woman who has struggled to overcome awide variety of psychiatric symptoms, two of which are depression andpre-menstrual syndrome (PMS). After several treatments, it wasdetermined that a combination of paroxetine 20 mg t.i.d. and lithium 300mg t.i.d. diminished her symptoms of obsessive-compulsive disorder,depression, hypomania and PMS. While taking this combination, she ratedher PMS as moderate to severe and barely tolerable. See the chart morefully set forth in FIG. 6.

In FIGS. 6-8 the abbreviations for each symptom on the graphs may betranslated as follows:

dep=depression

anx=anxiety

lab mood=mood swings

ang=anger

dec int=decreased interest in activities

con=difficulty in concentrating

en=lack of energy, fatigue

fd=food cravings

slp=sleep disturbance

con=loss of control

phy=physical symptoms (i.e., breast swelling)

impair =impaired in work, school, relationships

Patient No. 4's formal diagnoses were multiple personality disorder,obsessive-compulsive disorder, major depression disorder, alcoholism(recovering), and pre-menstrual syndrome (PMS).

Set forth below in Table 1 are the research criteria set forth in theDiagnostic and Statistical Manual of Mental Disorders, Forth edition,published by the American Psychiatric Association for Pre-MenstrualDysphoric Disorder, or Pre-Menstrual Syndrome.

                  TABLE 1    ______________________________________    Research Criteria for Pre-Menstrual Dysphoric Disorder    ______________________________________    A.   In most menstrual cycles during the past year, five (or more) of         the following symptoms were present for most of the time during         the last week of the luteal phase, began to remit within a         few days after the onset of the follicular phase, and were         absent in the week postmenses, with at least one of the         symptoms being either (1), (2), (3) or (4):     (1)     markedly depressed mood, feelings of hopelessness,             or self-deprecating thoughts;     (2)     marked anxiety, tension, feelings of being "keyed up,"             or "on edge";     (3)     marked affective lability (e.g., feeling suddenly sad or             tearful or increased sensitivity to rejection);     (4)     persistent and marked anger or irritability or increased             interpersonal conflicts;     (5)     decreased interest in usual activities (e.g., work, school,             friends, hobbies);     (6)     subjective sense of difficulty in concentrating;     (7)     lethargy, easy fatigability, or marked lack of energy;     (8)     marked change in appetite, overeating, or specific             food cravings;     (9)     hypersomnia or insomnia;    (10)     a subjective sense of being overwhelmed or             out of control;    (11)     other physical symptoms, such as breast tenderness             or swelling, headaches, joint or muscle pain,             a sensation of "bloating," weight gain.    B.   The disturbance markedly interferes with work or school or with         usual social activities and relationships with others (e.g.,         avoidance of social activities, decreased productivity and         decreased efficiency at work or school.)    C.   The disturbance is not merely an exacerbation of the symptoms         of another disorder, such as Major Depressive Disorder, Panic         Disorder, Dysthymic Disorder, or a Personality Disorder         (although it may be superimposed on any of these disorders.)    D.   Criteria A, B and C must be confirmed by prospective daily         ratings during at least two consecutive symptomatic         cycles. (The diagnosis may be made provisionally prior to         this confirmation).    ______________________________________     Note: In menstruating females, the luteal phase corresponds to the period     between ovulation and the onset of menses, and the follicular phase begin     with menses. In nonmenstruating females (e.g., those who have had a     hysterectomy), the timing of luteal and follicular phases may require     measurement of circulating reproductive hormones.

Patient No. 4 had a history of severe PMS that started when she was 30years old. She described a typical menses as follows. She was usuallymoderately to severely depressed for at least two days during the weekbefore her menses. She had sudden mood swings. One moment she would becrying and the next she would be laughing wildly, or she would havesudden outbursts of anger. She was markedly tense and would fidgetconstantly. She tired easily and lacked energy. She could barely dragherself out of bed each morning. She craved carbohydrates and oftenwould eat several doughnuts, whole cakes, or boxes of cookies. She sleptlittle, and for two or three nights she would have night sweats thatdrenched her bed. She also experienced back cramps, bloating and painsin her joints and muscles. She had trouble concentrating and was unableto do life's simplest chores. Her PMS interfered with her ability tofunction. She lost interest in her favorite hobby, reading.

She was prescribed paroxetine because of its documented efficacy in thetreatment of obsessive-compulsive disorder. Patient No. 4 also noticedthat it reduced the severity of her symptoms of PMS from severe tomoderately severe. The chart in FIG. 6 depicts patient No. 4's rating ofher late luteal phase symptoms during a month. During this month, shewas taking paroxetine 20 mg t.i.d. and 300 mg of lithium t.i.d. Shedescribed this as typical of the menstrual cycles she has while takingparoxetine. Paroxetine decreased the severity of her symptoms but didnot eliminate them. It had little to no effect on her energy level,carbohydrate craving and other physical symptoms.

Due to a gastrointestinal disturbance that lasted approximately sixweeks, patient No. 4 was unable to take the paroxetine and lithiumcombination as described above for approximately three weeks. Her"black" depression returned and she frequently thought of suicide. Whileoff paroxetine and lithium, her PMS was severe. It reminded her of themenses she had experienced before she started paroxetine. FIG. 7 depictspatient No. 4's rating of her symptoms of pre-menstrual symptoms duringthe late luteal phase of her menstrual cycle wherein she had not takenany of the medication in three weeks. This depicts that this menses wasone of the more severe ones that she had experienced and was typical ofher menses before taking paroxetine.

After her gastrointestinal symptoms subsided, she was left weak, frail,dizzy, depressed and crippled by hand-washing and other rituals thatcharacterized her obsessive-compulsive disorder. She resumed lithium 300mg t.i.d. and paroxetine 40 mg per day, but her depression wasrefractory. The inventor then suggested that she begin taking chromiumpicolinate. At the time of the suggestion, her plasma contained nodetectable chromium.

About a week later, she started taking chromium picolinate at a dosageproviding 200 μg of chromium twice a day. She started taking chromiumpicolinate in this amount on the fourth day of menstruation. Thus, shewould expect her pre-menstrual syndrome to begin approximately two weeksafter beginning to take chromium picolinate.

However, she was not aware of any of the symptoms of pre-menstrualsyndrome (except for breast swelling). She was surprised at the onset ofmenses. For the first time in her recent memory, she was completelywithout signs or symptoms of PMS, except for breast swelling. Though sheexperienced breast swelling, she did not experience breast tenderness.The chart presented in FIG. 8 depicts patient No. 4's rating of hersymptoms of PMS while taking paroxetine 20 mg t.i.d., lithium 300 mgt.i.d., and chromium picolinate providing 200 μg of chromium b.i.d. Heronly symptoms were a slight sleep disturbance and breast swelling.Patient No. 4 noted that this was the least troublesome menses that shehad experienced in 15 years.

Thus, an aspect of the present invention includes the treatment ofpre-menstrual syndrome (PMS) comprising administering chromium in apreferred dose of 200 μg b.i.d. to a patient in need thereof.Additionally, as paroxetine is a selective serotonin reuptake inhibitorand an antidepressant, it is an aspect of this invention to improve theeffectiveness in administering such a composition for the treatment ofpre-menstrual syndrome.

Therefore, the present invention relates to a treatment of depression inmen and women and to a treatment of pre-menstrual syndrome (PMS) inwomen using chromium, in a preferred form of chromium picolinate, aloneor in conjunction with an antidepressant composition, such as aselective serotonin reuptake inhibitor (SSRI). Chromium potentiates theaction of SSRI's and relieves the dysphoria in depression and PMS,reduces or eliminates other symptoms of depression (including cravingfor carbohydrates, exhaustion and muscle aches), reduces the lag timebetween administration of SSRI's and clinical response, and reduces theside effects of SSRI's. Further, chromium is neurobiologically activeand acts independently of the antidepressant composition, such as anSSRI.

It will be understood that various details of the invention may bechanged without departing from the scope of the invention. Furthermore,the foregoing description is for the purpose of illustration only, andnot for the purpose of limitation--the invention being defined by theclaims.

What is claimed is:
 1. A method of improving the effectiveness of aselective serotonin reuptake inhibitor composition as a treatment forpre-menstrual syndrome, comprising administering a compositionconsisting essentially of a therapeutically effective amount of chromiumin a pharmaceutically acceptable form to a patient during a time inwhich the patient is taking the selective serotonin reuptake inhibitorcomposition as a treatment for pre-menstrual syndrome.
 2. The methodaccording to claim 1 wherein the pharmaceutically acceptable formcomprises chromium picolinate.
 3. The method according to claim 1wherein the selective serotonin reuptake inhibitor is selected from thegroup consisting of sertraline, fluoxetine, paroxetine, fluvoxamine, andcombinations thereof.
 4. The method according to claim 1 whereinchromium is administered in a dose ranging from about 50 μg to about1,000 μg daily.
 5. The method according to claim 4 wherein chromium isadministered in a dose ranging from about 100 μg to about 600 μg daily.6. The method according to claim 5 wherein chromium is administered in adose ranging from about 200 μg to about 500 μg daily.
 7. The methodaccording to claim 1 wherein the therapeutically effect amount isadministered at least once a day.
 8. The method according to claim 1wherein the therapeutically effect amount is administered at least twicea day.
 9. The method according to claim 1 wherein the therapeuticallyeffect amount is administered three times a day.
 10. A method ofimproving the effectiveness of a selective serotonin reuptake inhibitorcomposition as a treatment for pre-menstrual syndrome, comprisingadministering a composition consisting essentially of a therapeuticallyeffective amount of chromium in a pharmaceutically acceptable form to apatient during a time in which the patient is taking the selectiveserotonin reuptake inhibitor composition as a treatment forpre-menstrual syndrome, wherein chromium is administered in a doseranging from about 1 μg to about 10 μg per kilogram body weight of thepatient daily.
 11. The method according to claim 10, wherein chromium isadministered in a dose ranging from about 2 μg to about 8 μg perkilogram body weight of the patient daily.
 12. The method according toclaim 11, wherein chromium is administered in a dose ranging from about4.5 μg to about 6 μg per kilogram body weight of the patient daily.